Many pharmaceutical drug products are sensitive to moisture and require dry storage environment to preserve their activity. Some of the newer drug formulations are also sensitive to ambient oxygen, presence of which in the package can cause rapid oxidation of essential product components, often resulting in a loss of activity and a reduced shelf life of the product. Common pharmaceutical products include tablets, capsules, gelcaps, and other solid single dosage formulations, usually referred to as “tablets”. Storage requirements to packaging of many pharmaceutical products often include at least a two year shelf life requirement. A blister pack such as shown in FIG. 1 provides a convenient way to encapsulate an individual tablet between metallic foil and heat sealable plastic sheet, which is thermoformed to create a set of cavities for packaging each tablet in its own individual cavity. Such blister packs allow for dispensing individual tablets from the package without exposing other tablets in the pack to the external environment.
Oxygen present inside the product, the package headspace and the package walls after sealing the package is referred to as residual oxygen. The oxidative deterioration of the packaged product can be slowed and/or delayed by using high “passive” barrier packaging materials and structures and by combining them with modified atmosphere packaging methods such as vacuum packing and/or headspace flushing with inert gas before sealing. The passive barrier to oxygen permeation acts as a physical barrier that reduces or eliminates the diffusive oxygen transport through the container wall but does not chemically interact with oxygen. These methods of protection are often insufficient to provide the required storage duration and prevent the loss of product activity.
Early “active” packaging methods of extending shelf life of oxygen sensitive products by maintaining low oxygen environment inside a package included placing chemically reactive oxygen absorbers inside a package. Materials capable of absorbing oxygen in the course of chemical reactions irreversible at the storage conditions are commonly referred to as oxygen scavengers. Oxygen scavengers enclosed inside the package in the form of separate packets, pouches or sachets reduce the residual oxygen amounts and react with permeated oxygen, however they are unable to prevent oxygen ingress through the container walls via ordinary diffusion. Therefore an additional barrier protection in the form of high passive barrier materials characterized by low oxygen permeability in them is often required. The oxygen permeated through packaging is then competitively consumed by the scavenger and by the oxygen sensitive product. For highly unstable products the excessively high reactivity of the enclosed scavenger with oxygen is often required to prevent preferential oxidation of the packaged product. The potential ingestion of the packets or their contents by pets, children and adult consumers is an issue with the use of packets.
In view of limitations of enclosed oxygen scavengers, it has been proposed to incorporate oxygen scavengers into a packaging material forming container walls. Such structures are referred to as “active barriers” to oxygen permeation because they not only physically restrict the rates of oxygen diffusion across the barrier but also chemically react with permeating oxygen thus further reducing the effective rates of oxygen permeation. Such active barriers are also advantageous because they can potentially absorb oxygen trapped inside the package similar to enclosed absorbers. As noted by Solovyov and Goldman [Int. J. Polym. Mater. 2005, vol. 54, pp. 71-91]; the lowest oxygen transmission rates and the largest barrier improvement are obtained when the rapidly reacting oxygen scavenging species is placed within the highest barrier matrix material, specifically, the material with the lowest oxygen diffusivity in it. The barrier improvement factor is defined as the ratio of the effective oxygen flux through the active barrier layer to that through the passive barrier layer made from essentially the same matrix material. Thus, the barrier improvement factor characterizes the relative permeation rate reduction due to chemical reaction rather than the barrier function of a structure alone. The notion of the effective flux refers to the net diffusive mass transfer rate across the downstream boundary of the barrier (i.e., the boundary exposed to the package contents). PVOH (polyvinyl alcohol polymer), EVOH (ethylenevinyl alcohol copolymer) and certain polyamide resins are the examples of such high passive barrier polymeric materials suitable as polymeric matrixes for loading an oxygen scavenging species and for making highly efficient reactive barriers. However, the oxygen barrier function of PVOH and EVOH materials is known to rapidly degrade as the relative humidity of their environment increases. Therefore, such materials cannot be used alone to form an oxygen barrier structure and they often have to be protected from moisture diffusion by additional water vapor barrier layer(s), e.g., made from polyolefins.
When oxygen is present on both sides of the barrier, the reactive barrier can potentially absorb it from both sides resulting in reduction of residual oxygen amount trapped inside the package after sealing. The condition for this effect to occur was derived by Solovyov and Goldman [ibid.] for homogeneously reactive single layer barrier. Polymeric materials such as PVOH and EVOH suited for making the most efficient reactive barriers to oxygen permeation are in the same time poorly suited as matrixes for rapid absorption of headspace oxygen from inside the package by the loaded scavenger. The reason is that low oxygen solubility and low oxygen diffusion rates in such materials prevent efficient transport of oxygen to the scavenging reactive sites within the matrix. The resulting rates of oxygen sorption into the matrix are too low to efficiently remove residual headspace oxygen. Moreover, these sorption rates are progressively reduced as the oxygen scavenger is consumed or deactivated by the localized reaction-diffusion wave (similar to reaction-diffusion combustion wave consuming solid fuel rod) propagating from inside the package across the reactive wall thickness. There is a need to overcome this problem and to achieve efficient scavenging of both oxygen permeating from the external environment and residual oxygen present in the package after sealing.
In design of pharmaceutical packaging a common way to achieve an ultimate gas barrier is to make individual cavities from metallic foil rollstock sealed to another foil rollstock. To seal the foil package, one or both upper and lower foil rollstocks are usually coated with an adhesive sealant. Such packages are not what is commonly understood as blister packs, as they suffer from the lack of transparency and a well-defined geometrical shape around the encapsulated tablet, in effect forming a minipouch for each tablet. As a result it is not immediately obvious for a consumer to observe whether the individual pouch still contains a tablet or not. On the other hand, thermoformed rigid or semi-rigid transparent plastic sheet heat-sealed to a foil rollstock to form a blister pack such as in FIG. 1, while preferred by consumers due to dispensing convenience and product visibility, forms a blister pack that often suffers from high rates of water vapor and oxygen permeation through the plastic. There is a need to alleviate high oxygen permeability of plastic sheet materials making them suitable for manufacturing extended shelf life blister packs.
In making pharmaceutical blister pack, multiple cavities are formed in the thermoplastic polymer sheet via one of the known thermoforming techniques. When multilayer sheet structures are used to improve gas barrier properties of the blister, the layered structure design, materials selection for each layer, and the thermoforming process parameters such as the sheet preheat time, the forming temperature, the rate of forming and the forming technique have to be adjusted to facilitate deformation of the structure into a desired shape, improve production rates and at the same time reduce film shrinkage and prevent overheating and resulting degradation and thermal decomposition of polymeric layer materials. These goals often require using plastic layer materials with overlapping thermal processing windows, i.e., not every polymeric material pair can be used as a thermoformable substrate for blister packs.
Many organic and inorganic oxygen scavenging compositions and their combinations have been proposed. These compositions are distinguished by whether an organic or inorganic substrate forming a part of the composition is oxidized by permeating oxygen. Inorganic oxygen scavengers are commonly based on oxidation of reduced transition metals, sulfites to sulfates, and other similar chemistries such as U.S. Pat. Nos. 5,262,375 (McKedy 1993), 5,744,056 (Venkateshwaran et al. 1998), 2,825,651 (Loo and Jackson 1958), 3,169,068 (Bloch 1965), 4,041,209 (Scholle 1977). Described organic oxygen scavengers are based on oxidation of carbon-carbon double bonds in polymer chain backbones and pendant groups (ethylenic unsaturation subject to autooxidation), transition metal catalyzed oxidation of certain polyamides, oxidation of certain photo reduced quinones, oxidation of ascorbates, butylated hydroxyanisoles (BHA), butylated hydroxytoluene (BHT), enzymes, certain organo-metallic ligands, and others such as WO 02/076,916 (Horsham et al.), U.S. Pat. No. 6,517,728 (Rooney), U.S. Pat. No. 6,123,901 (Albert), U.S. Pat. No. 6,601,732 (Rooney), WO 04/055,131 (Scully et al.), and WO 02/051,825 (Horsham et al.) While transition metal-based inorganic scavengers often have larger reactive capacities to absorb oxygen per unit weight of the composition, organic oxygen scavengers are preferable in many instances due to their ability to be blended or covalently attached to the passive barrier polymer without introducing undesirable color, loss of transparency, and degradation of mechanical and/or consumer properties of the barrier polymer structure. Depending on the chemical structure of the organic scavenger and the matrix polymer, oxygen scavenging species can be dispersed in the matrix during compounding or covalently bonded to the matrix polymer as described in U.S. Pat. Nos. 5,627,239, 5,736,616, 6,057,013, WO 99/48963 by Ching et al. (1997-2000). The latter arrangement is preferable because low molecular weight oxidation byproducts often present in the barrier after the scavenging reaction completion can migrate into the package and cause undesirable contamination of the product or affect its properties in another negative way. In order to prevent the migration of oxidation reaction byproducts, both the scavenging species and the reaction products are advantageously preferred to be covalently bonded to the matrix polymer. Oxygen scavenging species not bonded to the matrix polymer are also often unsuitable for contact with the product intended for human consumption due to the reasons described above and a respective lack of country-specific regulatory approvals. Such scavenging species often have to be placed into separate layers of the barrier structure that are insulated from the product by passive barrier layer(s) to reduce or prevent byproduct migration.
In U.S. Pat. No. 6,646,175—Yang et al., U.S. Pat. No. 5,350,622—Speer, and U.S. Pat. No. 6,569,506—Jerdee and WO 98/12127 there are materials disclosed with more than one oxygen scavenging layer. In U.S. Pat. No. 6,682,791 McKnight discloses packages and packaging structures with at least two oxygen scavenging materials having different oxygen scavenging properties and arranged as layers within the packaging structure. A difference in oxygen scavenger and/or catalyst concentration between the layers is envisioned.
There remains a need for an oxygen absorbing structure suitable for the rapid (e.g., within hours) absorption of residual headspace oxygen and providing efficient oxygen absorption and a high barrier to oxygen permeation for long term storage (e.g., multiple years) in packaging articles such as blister packs.